Huntington's Disease (HD)
Huntington's disease (HD) is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disorders. Our company is committed to providing our clients with a range of disease modeling services and in vivo animal studies to provide reliable preclinical research data.
Overview of Huntington's Disease (HD)
Huntington's disease (HD) is a rare neurodegenerative disorder that affects approximately 1 in 10,000 people worldwide. The genetic basis of HD lies in an abnormal expansion of CAG trinucleotide repeats in the huntingtin (HTT) gene, leading to the production of mutant huntingtin protein (mHTT). The abnormally expanded polyglutamine tract in the mHTT protein disrupts various cellular processes, resulting in toxic aggregate formation, mitochondrial dysfunction, apoptosis, and transcriptional dysregulation.
The mHTT protein exerts its toxic effects through a gain-of-function mechanism, leading to disruptions in neuronal physiology, atrophy in specific brain regions such as the basal ganglia, cortical areas, and white matter, and eventual widespread neuronal loss across the brain. Dysregulation of ubiquitin/proteasome and autophagy systems contributes to the accumulation of toxic protein aggregates, while oxidative stress and inflammation further exacerbate the disease progression.
Fig.1 Diagram of Huntington's disease pathogenesis and possible therapeutic targets. (Tabrizi, Sarah J., et al., 2022)Animal Models of HD
Many animal models have been developed to study HD, with rodents, particularly mice, being commonly used. These models can be broadly categorized as transgenic truncated models, transgenic full-length models, and knock-in models.
Truncated models: the first models to be developed were the R6 transgenic mouse lines (R6/1 and R6/2), which express different levels of the mHTT gene fragment with varying numbers of CAG repeats.
Full-length transgenic models: such as the YAC128 and BACHD lines, express the entire mHTT gene with a large number of CAG repeats. These models develop progressive motor deficits, synaptic dysfunction, and atrophy in brain regions, resembling aspects of HD progression in humans.
Knock-in models: such as the zQ175 line, have also been developed, exhibiting motor symptoms, cognitive deficits, weight loss, and neuropathological changes characteristic of HD.
Therapeutics Development of HD
- Targets of HD Therapy Development
HTT Gene Regulation: One of the main targets in HD therapy development is the regulation of the HTT gene expression. Various strategies such as RNA interference (RNAi) and Antisense Oligonucleotide (ASO) compounds are being explored to target and degrade the mutant HTT mRNA, thereby reducing the production of toxic mHTT protein.
Proteasomal Degradation: Therapeutic interventions aimed at enhancing proteasomal degradation of mHTT have shown promise in preclinical models. These strategies focus on promoting the clearance of toxic protein aggregates.
Caspase Inhibition: Inhibiting caspase activities, such as caspase-3 and caspase-1, have been investigated as a potential therapeutic strategy in HD. Compounds like Minocycline have shown neuroprotective effects by preventing caspase-mediated cell death and improving disease phenotype.
- Types of HD Therapy Development
Gene Therapy Development: Recent advancements in genome editing technologies, such as CRISPR/Cas9, provide opportunities for precise modifications in the HTT gene. These technologies hold promise in developing gene therapies that can target the root cause of HD by correcting the genetic mutations responsible for the disease.
Drugs Targeting Excitotoxicity: Drugs like Memantine, an NMDA receptor antagonist, have shown efficacy in reducing striatal cell death and preserving cognitive functions in HD. Therapeutic compounds that modulate excitotoxic pathways represent a potential avenue for symptom management in HD.
Our Services
HD Therapeutic Development Services: By leveraging cutting-edge technologies and expertise in molecular biology, our company is committed to developing novel therapeutic interventions. Our comprehensive therapy development services span various modalities such as small molecule drug, cell therapy, gene therapy, therapeutic antibody, therapeutic peptide, and therapeutic protein. We utilize state-of-the-art technologies and methodologies to accelerate the discovery and development of potential therapeutics for HD.
HD Animal Model Service: We are committed to providing our clients with a variety of HD animal models and assessing the translational potential of animal models based on their construct, face, and predictive validity. We select the right animal model for our clients based on the strengths of the various model systems and our knowledge of the phenotypes and endpoints characterized in these models. Our animal models include, but are not limited to:
- Transgenic C. elegans models
Truncated HTT N-terminal fragment models: HtnQ95, HtnQ150, Htt57Q88, Htt57Q128 - D. melanogaster models
Truncated HTT N-terminal fragment models: HttQ75, HttQ120, Httex1pQ93, Htt128Q, N-termHttQ128
Full-length HTT models: Htt128QFL - Rodent models
Truncated N-terminal fragment models: R6/1 mice, R6/2 mice, N171-Q82 mice, HD94 mice, Shortstop mice, N118- 82Q mice, N586- 82Q mice, Ubi-G-HTT84Q mice, HD51 rats
Knock-in models: CAG140 mice, HdhQ92 mice, HdhQ111 mice, HdhQ150 mice, HdhQ200 mice, Hdh4/Q72 mice, Hdh4/Q80 mice, zQ175 mice
Transgenic models: HD48 mice, HD89 mice, YAC128 mice, YAC48 mice, YAC72 mice, BACHD mice, Hu97/18 mice, iFL148Q mice, BACHD rats - Large animal models
Sheep models: OVT73 transgenic mHTT sheep, knock-in mHtt sheep
Minipig models: transgenic mHTT minipig, KI-HD-85Q knock-in mHtt minipig, KI-HD-150Q knock-in mHtt minipig
Nonhuman primate (NHP) models: AAV-mHTT somatic models, knock-in mHTT NHP
Reference
- Tabrizi, Sarah J., et al. "Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities." The Lancet Neurology 21.7 (2022): 645-658.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.